RESUMO
Granulomatous slack skin (GSS) is an extremely rare subtype of cutaneous T-cell lymphoma accompanied by an abundant number of macrophages and is clinically characterized by the development of pendulous skin folds. However, the characteristics of these macrophages in GSS remain unclear. Here, we conducted a spatial transcriptomic study on one frozen GSS sample and drew transcriptomic maps of GSS for the first time. Gene expression analysis revealed the enrichment of three clusters with macrophage transcripts, each exhibiting distinct characteristics suggesting that their primary composition consists of different subpopulations of macrophages. The CD163+ /CD206+ cluster showed a tumor-associated macrophage (TAM) M2-like phenotype and highly expressed ZFP36, CCL2, TNFAIP6, and KLF2, which are known to be involved in T-cell interaction and tumor progression. The APOC1+ /APOE+ cluster presented a non-M1 or -M2 phenotype and may be related to lipid metabolism. The CD11c+ /LYZ+ cluster exhibited an M1-like phenotype. Notably, these cells strongly expressed MMP9, MMP12, CHI3L1, CHIT1, COL1A1, TIMP1, and SPP1, which are responsible for extracellular matrix (ECM) degradation and tissue remodeling. This may partially explain the symptoms of cutaneous relaxation in GSS. Further immunohistochemistry on four GSS cases demonstrated that CD11c predominantly marked granulomas and multinucleated giant cells, whereas CD163 was mainly expressed on scattered macrophages, appearing as a mutually exclusive pattern. The expression pattern of MMP9 overlapped with that of CD11c, implying that CD11c+ macrophages may be a source of MMP9. Our data shed light on the characteristics of macrophages in the GSS microenvironment and provide a theoretical basis for the application of MMP9 inhibitors to prevent cutaneous relaxation of GSS. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Metaloproteinase 9 da Matriz , Neoplasias Cutâneas/genética , Microambiente Tumoral , Transcriptoma , Linfoma Cutâneo de Células T/complicações , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/patologia , Macrófagos/patologia , Perfilação da Expressão GênicaRESUMO
BACKGROUND: The molecular pathogenesis of endometrial cancer is not completely understood. CypB upregulated in many cancers, however, its role in endometrial carcinoma has not been studied. Here, we determine the effect of CypB on the growth of endometrial cancer. METHODS: In this study, we examined the expression of CypB in endometrial cancer tissues using immunohistochemistry. CypB silenced in HEC-1-B cell line by shRNA. CCK-8, colony formation assays, wound healing assays, and transwell analysis were performed to assess its effect on tumor cell proliferation and metastasis. Furthermore, microarray analysis was carried out to compare the global mRNA expression profile between the HEC-1-B and CypB-silenced HEC-1-B cells. Gene ontology and KEGG pathway enrichment analysis were performed to determine the potential function of differentially expressed genes related to CypB. RESULTS: We found that CypB was upregulated in endometrial cancer, inhibit CypB expression could significantly suppress cell proliferation, metastasis, and migration. We identified 1536 differentially expressed genes related to CypB (onefold change, p < 0.05), among which 652 genes were upregulated and 884 genes were downregulated. The genes with significant difference in top were mainly enriched in the cell cycle, glycosphingolipid biosynthesis, adherens junctions, and metabolism pathways. CONCLUSION: The results of our study suggest that CypB may serve as a novel regulator of endometrial cell proliferation and metastasis, thus representing a novel target for gene-targeted endometrial therapy. TRIAL REGISTRATION: YLYLLS [2018] 008. Registered 27 November 2017.
Assuntos
Neoplasias do Endométrio/genética , Proliferação de Células , Ciclofilinas/genética , Feminino , Humanos , Metástase NeoplásicaRESUMO
Persistently activated IL-6/STAT3 pathway promotes acquired resistance to targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC) treatment. miR-206 has been verified to be dysregulated and plays as a negative regulator in lung cancer. However, whether miR-206 may overcome IL6-induced gefitinib resistance in EGFR-mutant lung cancer remains elusive. In this study, we investigated the role of miR-206 in IL6-induced gefitinib-resistant EGFR-mutated lung cancer cell lines. We showed that forced miR-206 expression restored gefitinib sensitivity in IL6-induced gefitinib-resistant EGFR-mutant lung cancer cells by inhibiting IL6/JAK1/STAT3 pathway. Specifically, mechanistic investigations revealed that miR-206 blocked IL-6/STAT3 signalling via directly targeting the 3'-UTR of intracellular IL-6 messenger RNA. Moreover, IL-6 induced miR-206 down-regulation by reducing the cropping process of primary miR-206 (pri-miR-206) into the Drosha/DGCR8 complex. Taken together, our findings reveal a direct role of miR-206 in regulating IL-6/STAT3 pathway and contrarily activated IL-6/STAT3 signalling mediates the miR-206 maturation process in gefitinib-resistant EGFR-mutant lung cancer cells.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Interleucina-6/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Regiões 3' não Traduzidas/genética , Idoso , Linhagem Celular Tumoral , Regulação para Baixo/genética , Receptores ErbB/genética , Feminino , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Renal cell carcinoma (RCC) is the third most common urological cancer with highly metastatic potential. MAGI1 plays an important role in stabilization of the adherens junctions and has been confirmed to suppress invasiveness and metastasis in multiple cancers in clinic. However, its expression and anti-metastatic ability in RCC are still unclear. In this study, we demonstrated that MAGI1 was markedly decreased in the RCC and indicated poor survival. Furthermore, we found that MAGI1 suppressed the invasion and migration of human RCC cells. Mechanistic investigations revealed that MAGI1 stabilized the PTEN/MAGI1/ß-catenin complex to inhibit ß-catenin signaling pathway. Moreover, MAGI1 was targeted by miR-520h which was transcriptionally activated by c-Myb. Collectively, our findings suggested that MAGI1mediated tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in RCC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma de Células Renais/metabolismo , Moléculas de Adesão Celular/metabolismo , Guanilato Quinases/metabolismo , Neoplasias Renais/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Guanilato Quinases/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myb/genética , Transdução de Sinais/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMO
PURPOSE: To investigate the differential gene expression pattern between invasive multifocal/multicentric (MMBC) and unifocal breast cancer (UFBC) with cDNA array and to discover the potential outlier genes associated with the incidence of MMBC and also to provide a guidance for clinical treatment and prognosis prediction. METHODS: This retrospective study analyzed the gene expression pattern alteration in breast cancer. We collected 156 MMBC (136 cases with 2 foci, 20 cases with 3 foci) and 130 UFBC samples from patients hospitalized in Yuhuangding Hospital, Yantai, from January 2005 to December 2015. The outlier genes were screened by cDNA expression microarray and validated by RT-PCR. RESULTS: 18 overexpressed and 22 underexpressed genes were identified in the differential analysis, including family genes ABCC11, ABCB5 and PRODH, PROL1. Noteworthily, ABCC11 was significantly upregulated, while ABCB3 was downregulated, which were confirmed by RT-PCR results. CONCLUSION: The differential expression pattern of ABCC11 and ABCB5 genes may serve as outliers, potentially associated with incidence of MMBS.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP , Neoplasias da Mama , Invasividade Neoplásica , Estadiamento de Neoplasias , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVE: Epigenetic changes in cancer and precancerous lesions could be utilized as biomarkers for cancer early detection. This study aims to investigate the novel biomarkers in endometrial carcinoma, and explore their epigenetic regulation. METHODS: Methylation of six tumor suppressor genes (CDH13, SHP1, HIN1, DKK3, CTNNA1 and PCDH8) was evaluated in 155 endometrium samples. Changes of methylation and mRNA expression after treatment with 5-Aza-2'-deoxycytidine (5-Aza-CdR) or/and trichostatin A (TSA) were investigated by MSP and qRT-PCR respectively. Co-immunoprecipitation was used to detect the interactions between UHRF1 and PRMT5 proteins. RESULTS: CDH13 and SHP1 promoters were highly methylated (81.36% and 86.44%, respectively) in endometrial carcinoma, while CDH13 promoter methylation was also present in complex hyperplasia and atypical hyperplasia (51.72% and 50.00%, respectively). Methylation of CDH13 and SHP1 promoters was associated with age and tumor differentiation or muscular infiltration depth. CDH13 and SHP1 promoters were completely methylated in endometrial carcinoma cell lines and were partially reversed by 5-Aza-CdR or TSA to induce mRNA levels (P<0.01). After combined treatment with these two agents, methylation of CDH13 and SHP1 promoters was completely reversed and expression of their mRNA was significantly increased (P<0.01). Moreover, PRMT5 could bind to UHRF1 and down-regulated by 5-Aza-CdR and/or TSA treatment (P<0.05). CONCLUSIONS: Our data demonstrate for the first time that SHP1 methylation has high specificity for diagnosis of endometrial carcinoma, while CDH13 promoter methylation plays a role in the earlier stage. Furthermore, UHRF1 could form a complex with PRMT5 to contribute to the endometrial carcinogenesis.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Caderinas/genética , Metilação de DNA , Neoplasias do Endométrio/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína-Arginina N-Metiltransferases/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Caderinas/biossíntese , Caderinas/metabolismo , Linhagem Celular Tumoral , Decitabina , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Genes Supressores de Tumor , Humanos , Ácidos Hidroxâmicos/farmacologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 6/biossíntese , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ubiquitina-Proteína Ligases , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: In this study, we examined the expression of human mammaglobin (hMAM) mRNA and the protein levels in patients with breast cancer and their relationship with prognostic clinicopathological parameters. METHODS: hMAM mRNA expression in leucocytes from peripheral blood samples from patients diagnosed with primary invasive breast cancer (IC), carcinoma in situ (CIS), or benign breast diseases was analyzed using RT-PCR. The hMAM protein levels and expression patterns in tissue from 3 patient groups were evaluated by immunohistochemical staining, and several non-breast neoplasms were selected as negative controls, undergoing the same examination. RESULTS: The expression of hMAM mRNA was significantly higher in patients with IC or CIS compared to those with benign tumors (both<0.01). Immunohistochemical staining revealed similar results, where patients with IC or CIS had higher levels of hMAM protein (p<0.01 and p<0.01, respectively), while none of the negative controls expressed hMAM. Further analyses showed a strong correlation between hMAM protein/mRNA expression and clinicopathological factors, such as histological grade, clinical stage, and lymph node status, in patients with IC. CONCLUSION: The hMAM mRNA and protein expression profiles validate the potential of hMAM as a specific marker for breast cancer diagnosis and target treatment delivery.
Assuntos
Neoplasias da Mama/química , Mamoglobina A/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma in Situ/química , Feminino , Humanos , Imuno-Histoquímica , Mamoglobina A/análise , Prognóstico , RNA Mensageiro/análiseAssuntos
Diagnóstico Diferencial , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Sarcoma/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Adulto , Feminino , Humanos , Sarcoma/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologiaRESUMO
BACKGROUND: The spleen is thought to be central in regulating the immune system, a metabolic asset involved in endocrine function. Overwhelming postsplenectomy infection leads to a mortality rate of up to 50%. However, there is still controversy on performing subtotal splenectomy as treatment of splenomegaly due to portal hypertension in cirrhotic patients. In the present study, immunocytes and the indexes of splenic size, hemodynamics, hematology and immunology in the residual spleen were analyzed to support subtotal splenectomy due to splenomegaly. RESULTS: In residual spleen, T lymphocytes mainly were focal aggregation in the periarterial lymphatic sheath. While B lymphocytes densely distributed in splenic corpuscle. In red pulp, macrophages were equally distributed in the xsplenic cord and adhered to the wall of splenic sinus with high density. The number of unit area T and B lymphocytes of splenic corpuscle and marginal zone as well as macrophages of red pulp were obviously increased in the residual spleen, while the number of macrophages didn't be changed among the three groups in white pulp. While there were some beneficial changes (i.e., Counts of platelet and leucocyte as well as serum proportion of CD3+ T cells, CD4+ T cells, CD8+ T cells were increased markedly; serum levels of M-CSF and GM-CSF were decreased significantly; The proportion of granulocyte, erythrocyte, megakaryocyte in bone marrow were changed obviously; But serum IgA, IgM, IgG, Tuftsin level, there was no significant difference; splenic artery flow volume, portal venous diameter and portal venous flow volume, a significant difference was observed in residual spleen) in the clinical indices. CONCLUSION: After subtotal splenectomy with splenomegaly due to portal hypertension in cirrhotic patients, the number of unit area T and B lymphocytes, and MØ in red pulp of residual spleen increased significantly. However, whether increase of T, B lymphocytes and MØs in residual splenic tissue can enhance the immune function of the spleen, still need further research to confirm.
Assuntos
Cirrose Hepática , Linfócitos , Monócitos , Baço , Esplenectomia , Esplenomegalia , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Contagem de Leucócitos , Cirrose Hepática/sangue , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Fator Estimulador de Colônias de Macrófagos/sangue , Fator Estimulador de Colônias de Macrófagos/imunologia , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Estudos Retrospectivos , Baço/imunologia , Baço/metabolismo , Baço/patologia , Baço/cirurgia , Esplenomegalia/sangue , Esplenomegalia/imunologia , Esplenomegalia/patologia , Esplenomegalia/cirurgiaRESUMO
Endometriosis is a puzzling and debilitating disease that affects millions of women around the world. Ovary is the most common organ site involved by endometriosis. Despite various hypotheses about its cell of origin, uncertainty remains. On the basis of our clinicopathologic observations, we hypothesize that fallopian tube may contribute the histogenesis of ovarian endometriosis. To examine if the hypothesis, tubal origin of ovarian endometriosis, has scientific supporting evidence, we identified a set of novel genes, which are either highly expressed in the normal fallopian tube or in the endometrium through a gene differential array study. Among many differentially expressed genes, FMO3 and DMBT1 were selected as the initial biomarkers to test the hypothesis. These biomarkers were then validated in ovarian sections with foci of endometriosis by comparing their expression levels in the fallopian tube and the endometrium within the same patients with real-time PCR, western blot and immunohistochemistry analysis. FMO3 was highly expressed in the tubal epithelia while low in the paired endometrium. In contrast, DMBT1 was high in the endometrium but low in the fallopian tube. In 32 ovarian endometriosis cases analyzed by real-time PCR, 18 (56%) showed a high level of FMO3 and a low level of DMBT1 expression. However, 14 (44%) endometriosis cases showed a reversed expression pattern with these two markers. Results were similarly seen in the methods of western blot and immunohistochemistry. The findings suggest that approximately 60% of the ovarian endometriosis we studied may be derived from the fallopian tube, whereas about 40% of the cases may be of endometrial origin. The fallopian tube epithelia may represent one of the tissue sources contributing to ovarian endometriosis. Such novel findings, which require confirmation, may have a significant clinical impact in searching for alternative ways of prevention and treatment of endometriosis.
Assuntos
Linhagem da Célula , Endometriose/patologia , Endométrio/patologia , Células Epiteliais/patologia , Tubas Uterinas/patologia , Doenças Ovarianas/patologia , Adulto , Western Blotting , Proteínas de Ligação ao Cálcio , Proteínas de Ligação a DNA , Endometriose/genética , Endometriose/metabolismo , Endométrio/química , Células Epiteliais/química , Tubas Uterinas/química , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Doenças Ovarianas/genética , Doenças Ovarianas/metabolismo , Oxigenases/análise , Oxigenases/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular/análise , Receptores de Superfície Celular/genética , Proteínas Supressoras de TumorRESUMO
BACKGROUND: E2F1 transcription factor plays a vital role in the regulation of diverse cellular processes including cell proliferation, apoptosis, invasion and metastasis. E2F1 overexpression has been demonstrated in small cell lung cancer (SCLC), and extensive metastasis in early phase is the most important feature of SCLC. In this study, we investigated the involvement of E2F1 in the process of invasion and metastasis in SCLC by regulating the expression of matrix metalloproteinases (MMPs). METHODS: Immunohistochemistry was performed to evaluate the expression of E2F1 and MMPs in SCLC samples in a Chinese Han population. The impact of E2F1 on invasion and metastasis was observed by transwell and wound healing experiments with depletion of E2F1 by specific siRNA. The target genes regulated by E2F1 were identified by chromatin immunoprecipitation (ChIP)-to-sequence, and the expressions of target genes were detected by real time PCR and western blotting. The dual luciferase reporter system was performed to analyze the regulatory relationship between E2F1 and MMPs. RESULTS: E2F1 is an independent and adverse prognosis factor that is highly expressed in SCLC in a Chinese Han population. Knockdown of E2F1 by specific siRNA resulted in the downregulation of migration and invasion in SCLC. The expressions of MMP-9 and -16 in SCLC were higher than other MMPs, and their expressions were most significantly reduced after silencing E2F1. ChIP-to-sequence and promoter-based luciferase analysis demonstrated that E2F1 directly controlled MMP-16 expression via an E2F1 binding motif in the promoter. Although one E2F1 binding site was predicted in the MMP-9 promoter, luciferase analysis indicated that this binding site was not functionally required. Further study demonstrated that E2F1 transcriptionally controlled the expression of Sp1 and p65, which in turn enhanced the MMP-9 promoter activity in SCLC cells. The associations between E2F1, Sp1, p65, and MMP-9 were validated by immunohistochemistry staining in SCLC tumors. CONCLUSIONS: E2F1 acts as a transcriptional activator for MMPs and directly enhances MMP transcription by binding to E2F1 binding sequences in the promoter, or indirectly activates MMPs through enhanced Sp1 and NF-kappa B as a consequence of E2F1 activation in SCLC.
Assuntos
Fator de Transcrição E2F1/genética , Metaloproteinase 16 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Proteínas Quinases/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Fator de Transcrição RelA/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Proliferação de Células , Fator de Transcrição E2F1/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas Quinases/genética , RNA Interferente Pequeno , Carcinoma de Pequenas Células do Pulmão/patologia , Fator de Transcrição RelA/genéticaRESUMO
PURPOSE: Vulvar squamous cell carcinoma (VSCC) contributes to about 3-5% of all gynecological cancers. Vulvar intraepithelial neoplasia (VIN) and vulvar lichen sclerosus (VLS) are regarded as precancerous lesions. Early detection and treatment of precancerous lesions may prevent development of VSCC. Osteopontin (OPN) has been shown to be involved in many physiological and pathological processes, such as tumor progression, by promoting cancer cell invasion and metastasis. As a result of these findings, OPN has been described as a potential marker for tumor progression in some malignancies. In this study, we investigated the expression of OPN in vulvar tissue specimens and compared its expression between different histopathological grades. METHODS: In the present study, the expression patterns of OPN in 80 paraffin-embedded tissue specimens, including 25 VSCC samples, 21 VIN lesions and 21 VLS, in addition to 13 normal vulvar samples, were examined by the immunohistochemical method and chromogenic in situ hybridization. RESULTS: The intensity of OPN expression steadily increased according to the pathological grades. In addition, OPN staining was found in the extracellular matrix in VSCC. CONCLUSIONS: Expression levels of OPN increased from VLS and VIN to VSCC, and steadily increased with the pathological stage of VSCC. Our results suggest that OPN may be associated with the progression of VSCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Osteopontina/metabolismo , Lesões Pré-Cancerosas/patologia , Neoplasias Vulvares/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/metabolismo , Progressão da Doença , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/metabolismo , Líquen Escleroso Vulvar/metabolismo , Líquen Escleroso Vulvar/patologia , Neoplasias Vulvares/metabolismoRESUMO
OBJECTIVE: The aim of this study was to explore whether postmortem hemorrhage can occur in brain tissue using rabbit models. METHODS: The rabbits killed by air embolism were randomly divided into the horizontal-position group and the upside-down group. Autopsy was performed after 48 hours, and the brains were investigated with macroscopic assessment and histologic examination. RESULTS: Macroscopically, congestion of vessels on the surface of the brain was identified in all the subjects in both groups. Microscopically, the presence of multifocal extravascular red blood cell aggregation was observed in brain parenchyma and subarachnoid space in the upside-down group. In contrast, no leakage of extravascular red blood cells was observed in the brain parenchyma and the subarachnoid space in the horizontal-position group. CONCLUSIONS: Hypostatic and leakage bleeding can occur in sites of subarachnoid space and brain parenchyma of rabbits after death by nonforce with a certain period and certain position of the placement. This type of hemorrhage is challenging to differentiate from traumatic hemorrhage in pathologic practice. To avoid misdiagnosis, the clinical pathologists should keep in mind that the possibility of postmortem hypostatic hemorrhage needs to be ruled out when the diagnosis of subarachnoid hemorrhage or cerebral hemorrhage is established.
Assuntos
Hemorragia Cerebral/patologia , Agregação Eritrocítica , Mudanças Depois da Morte , Hemorragia Subaracnóidea/patologia , Animais , Encéfalo/patologia , Patologia Legal , Masculino , Modelos Animais , Postura , CoelhosRESUMO
Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1ß, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.
Assuntos
Neoplasias Colorretais , Armadilhas Extracelulares , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Armadilhas Extracelulares/metabolismo , Linhagem Celular Tumoral , Neoplasias Hepáticas/metabolismo , Transdução de Sinais , Neoplasias Colorretais/genética , Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
OBJECTIVES: Objectively diagnosing non-erosive reflux disease (NERD) is still a challenge. We aimed to evaluate the use of in-vivo confocal laser endomicroscopy (CLE) to examine the microalterations of the esophagus in patients with NERD and its relationship with reflux episodes monitored by multiple intraluminal impedance-pH (MII-pH). METHODS: Patients with gastroesophageal reflux symptoms completed reflux disease questionnaires. NERD was determined by negative gastroscopy. Patients without reflux symptoms were recruited as controls. Pilot clinical study was followed by prospective controlled blinded study. All subjects were examined by white-light mode of the endoscopy followed by the standard CLE mode and then MII-pH monitoring. The microalterations seen on CLE images and the correlation between CLE features and reflux episodes were evaluated, the correlation between CLE and transmission electron microscope (TEM) data was also analyzed. RESULTS: On CLE images, NERD patients had more intrapapillary capillary loops (IPCLs) per image than did controls (8.29 ± 3.52 vs. 5.69 ± 2.31, P=0.010), as well as the diameter of IPCLs (19.48 ± 3.13 vs. 15.87 ± 2.21 µm, P=0.041) and intercellular spaces of squamous cells (3.40 ± 0.82 vs. 1.90 ± 0.53 µm, P=0.042). The receiver operating characteristic analysis indicated that IPCLs number (optimal cutoff >6 per image, area under the curve (AUC) 0.722, 95% confidence interval (CI) 0.592-0.853, sensitivity 67.7%, specificity 71.6%), IPCLs diameter (optimal cutoff >17.2 µm, AUC 0.847, 95% CI 0.747-0.947, sensitivity 81%, specificity 76%), and the intercellular spaces of squamous cells (optimal cutoff >2.40 µm, AUC 0.935, 95% CI 0.875-0.995, sensitivity 85.7%, specificity 90.5%) diagnosed NERD with reasonable accuracy. Combined features of dilatation of intercellular space plus increased IPCLs provided 100% specificity in the diagnosis of NERD patients. The intercellular spaces of squamous cells observed on CLE were highly related to that on TEM findings (r=0.75, P<0.001). Multivariate progressive regression analysis showed that acidic reflux, especially in the supine position, was related to the increased number and dilation of IPCLs in the squamous epithelium (ß=0.063, t=2.895, P=0.038 and ß=0.156, t=1.023, P=0.04). CONCLUSIONS: CLE represents a useful and potentially significant improvement over standard endoscopy to examine the microalterations of the esophagus in vivo. Acidic reflux is responsible for the microalterations in the esophagus of patients with NERD.
Assuntos
Esôfago/patologia , Refluxo Gastroesofágico/diagnóstico , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Adulto , Idoso , Área Sob a Curva , China , Impedância Elétrica , Monitoramento do pH Esofágico , Esôfago/metabolismo , Feminino , Refluxo Gastroesofágico/metabolismo , Refluxo Gastroesofágico/patologia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Análise Multivariada , Projetos Piloto , Postura , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: This study was designed to investigate the expression patterns of CEACAM1 and its relationship with angiogenesis in nonneoplastic and neoplastic gastric lesions. METHODS: CEACAM1 and TGF-ß expression was detected by immunohistochemical staining and dual-labeling immunohistochemical staining in neoplastic and nonneoplastic lesions. MVD-CD31 and MVD-CD105 were counted in CEACAM1-positive areas by dual-labeling immunohistochemistry. RESULTS: There was no expression of CEACAM1 in normal gastric mucosa. In IM and GIN, CEACAM1 was mainly expressed with membranous pattern. CEACAM1 was expressed with membranous pattern in well-differentiated adenocarcinoma, with cytoplasmic pattern in poorly differentiated adenocarcinoma, and with cytoplasmic and membranous pattern mixed together in intermediately adenocarcinoma. The expression patterns of CEACAM1 showed a significant difference (P < 0.05) in nonneoplastic and neoplastic lesions. Coexpression of CEACAM1 and TGF-ß was elevated and significantly different from nonneoplastic to neoplastic lesions (P < 0.05). Moreover, CEACAM1 and TGF-ß coexpression were related to carcinoma progression (r = 0.35; P < 0.05). MVD-CD31 and MVD-CD105 showed significant differences from nonneoplastic to neoplastic lesions (P < 0.05). CONCLUSIONS: CEACAM1 has different expression patterns in nonneoplastic and neoplastic lesions. The coexpression of CEACAM1 and TGF-ß increased from nonneoplastic to neoplastic lesions and may be related with tumor progression via promoting tumorous angiogenesis.
Assuntos
Antígenos CD/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Moléculas de Adesão Celular/metabolismo , Intestinos/patologia , Neovascularização Patológica/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Análise de Variância , Carcinoma in Situ/irrigação sanguínea , Distribuição de Qui-Quadrado , Endoglina , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/irrigação sanguínea , Metaplasia/metabolismo , Microvasos/metabolismo , Estadiamento de Neoplasias , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias Gástricas/irrigação sanguínea , Fator de Crescimento Transformador beta/metabolismoRESUMO
The aims of this study were to investigate the expression of SOX9 (sex determining region Y [SRY]-related high-mobility group box 9) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in benign, premalignant, and malignant gastric lesions and to explore the association between SOX9 and CEACAM1 in gastric carcinogenesis. SOX9 and CEACAM1 expression was detected in normal gastric mucosa, hyperplastic polyp, intestinal metaplasia, gastric intraepithelial neoplasia, and adenocarcinoma by immunohistochemistry. There was low expression of SOX9 and no CEACAM1 expression in normal gastric mucosa and hyperplastic polyps. Intestinal metaplasia began to express CEACAM1 and showed more membranous staining of CEACAM1 than normal mucosa and hyperplastic polyps (P = .000), but SOX9 expression had no significant difference, and the coexpression of SOX9 and CEACAM1 ascended; therefore, the difference was significant (P = .000). Gastric intraepithelial neoplasia showed more SOX9 expression, coexpression of SOX9, and CEACAM1 than in intestinal metaplasia (P = .014 and P = .026, respectively). Carcinoma showed more cytoplasmic CEACAM1 (P = .010), more SOX9 expression (P = .001), and more their coexpression (P = .023) than gastric intraepithelial neoplasia. As to the histologic classification, poorly differentiated carcinoma showed more cytoplasmic CEACAM1 than well and moderately differentiated carcinoma (P = .006 and P = .024, respectively). In the Laurén classification, diffuse carcinoma showed more cytoplasmic CEACAM1 than intestinal carcinoma (P = .0035), but the SOX9 expression and their coexpresison showed no difference (P = .065 and P = .074, respectively). With the elevation of SOX9 expression and the changing of CEACAM1 expression patterns, the coexpressions of SOX9 and CEACAM1 were highly elevated from benign proliferative lesions to malignant lesions. Moreover, the SOX9 expression and the coexpression with CEACAM1 were correlated positively (r = 0.310; P = .015). In addition, SOX9 expression was positively correlated with CEACAM1 expression patterns (r = 0.124; P = .032). In addition, CEACAM1 expression patterns and coexpression of SOX9 and CEACAM1 show significant difference between T1 and T2 and T3 and T4 (P = .021 and P = .011, respectively). Accordingly, compared with N0, N2 and N3 showed significant difference in SOX9 expression (P = .018), CEACAM1 expression patterns (P = .010), and their coexpression (P = .010). SOX9 expression significantly increased from nonneoplastic lesions to neoplastic lesions, and CEACAM1 expression patterns markedly changed; their coexpression also showed signally elevated suggesting that SOX9, as a transcriptional regulator, play important roles in the changing of CEACAM1 expression patterns, which might promote the tumor progression.
Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/metabolismo , Mucosa Gástrica/metabolismo , Lesões Pré-Cancerosas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patologia , Transformação Celular Neoplásica/metabolismo , Mucosa Gástrica/patologia , Humanos , Hiperplasia/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Metaplasia/metabolismo , Estadiamento de Neoplasias , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: The identification of gastric superficial cancerous lesions based on conventional white-light endoscopy (WLE) is challenging, and histological analysis remains the 'gold standard' for the final diagnosis. Confocal laser endomicroscopy (CLE) can provide in vivo histological observation without the need for biopsy. OBJECTIVE: To develop and evaluate CLE imaging criteria for gastric superficial cancerous lesions and to compare the diagnostic value of real-time integrated CLE (iCLE) and WLE alone in distinguishing gastric superficial cancerous lesions. DESIGN: Prospective study. SETTING: Qilu Hospital, Shandong University, Jinan, China. PATIENTS: A total of 182 patients were enrolled into phase I and 1786 patients were enrolled into phase II. INTERVENTIONS: CLE images were blindly evaluated after endoscopy in phase I, and real-time iCLE diagnosis during endoscopy was compared with WLE diagnosis by using histopathology as a gold standard in phase II. MAIN OUTCOME MEASUREMENTS: The validity and reliability of the CLE diagnosis for identifying gastric superficial cancerous lesions. RESULTS: Off-line CLE diagnosis for early gastric cancers had a high sensitivity (88.1%) and specificity (98.6%). When the two-tiered CLE classification of non-cancerous lesions and cancer/high-grade intraepithelial neoplasia (HGIN) lesions was introduced, CLE diagnosis led to a higher sensitivity (90.2%) and specificity (98.5%) (phase I). Real-time iCLE diagnosis had a higher sensitivity (88.9%), specificity (99.3%) and accuracy (98.8%) for gastric superficial cancer/HGIN lesions than WLE diagnosis (sensitivity, 72.2%; specificity, 95.1%; and accuracy, 94.1%) (p < 0.05) (phase II). Limitations This was a single-centre study. CONCLUSIONS: CLE can be used to identify gastric superficial cancer/HGIN lesions with high validity and reliability.
Assuntos
Carcinoma in Situ/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Feminino , Gastroscopia , Humanos , Masculino , Microscopia Confocal/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
AIMS: To investigate the correlation between CCND1 amplification and CHK1 deletion in breast cancer, and to explore their role in tumorigenesis and progression, a comparative study of the gene copy number changes of CCND1 and CHK1 was performed with dual-colour fluorescence in-situ hybridization (FISH). METHODS AND RESULTS: Sixty-one infiltrating ductal breast carcinomas with foci of ductal carcinoma in situ (DCIS) components were selected for dual-colour FISH. A strong correlation was found between CCND1 amplification and CHK1 deletion (P<0.0001). Fourteen cases were detected that demonstrated both CCND1 amplification and CHK1 deletion. Interestingly, when comparing the infiltrating and non-invasive areas for the same tumour, we found three cases with CCND1 amplification in the infiltrating areas but not in the DCIS areas. We did not find a CHK1 gene profile difference between infiltrating and DCIS areas in the same lesions. CONCLUSIONS: Our findings suggest that CCND1 amplification and CHK1 deletion are common events in breast cancer, and that the two genetic alterations often coexist. Our data also suggest that CHK1 deletion is an early genetic event in the development of breast cancer and can be detected at the DCIS stage, whereas CCND1 amplification is more likely to be associated with tumour progression.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Ciclina D1/genética , Proteínas Quinases/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Transformação Celular Neoplásica , Quinase 1 do Ponto de Checagem , Ciclina D1/metabolismo , Progressão da Doença , Feminino , Amplificação de Genes/genética , Deleção de Genes , Dosagem de Genes/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Proteínas Quinases/metabolismoRESUMO
Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p < 0.0001, Fischer's exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p < 0.0001, Fischer's exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.